Molecular mechanisms underlying blood development and disorders are of great interest and importance from the perspective of understanding normal function and leukemias. Drosophila has long served as a genetic model for many developmental processes, but its usefulness as a hematopoietic model has only recently been appreciated. The mechanisms that maintain blood stem cells in Drosophila show remarkable conservation in strategy of development and function with mammalian systems. The proposed work intends to determine the molecular pathways that maintain stem cell homeostasis. Also proposed is the role of systemic signals and nutrient deprivation on myeloid cell development. These are developmentally and medically relevant problems for which model systems amenable to genetic screens are essential to develop. The proposal has four specific aims. In Aim 1, a homeostatic model by which blood precursors are maintained not only by a signal from a niche, but also from the cells that have started differentiating will be developed. In Aim 2, the involvement of the transcription factor STAT in the maintenance of stem cell fate in Drosophila will be investigated. In Aim 3, the role of extracellular matrix components that control the integrity of stem cells will be studied. In the final aim, signals arising from the brain that control blood stem cell maintenance in Drosophila will be investigated and their role in starvation induced stem cell loss studied. PUBLIC HEALTH RELEVANCE: The genetic basis of blood development and disorders are extremely important to understand in order to make progress on understanding immune challenges and leukemias. The fruit fly, Drosophila is a model organism in which such studies can be achieved with great predictive power for the human condition. This proposal seeks to understand the molecular mechanisms by which blood stem cells are maintained, and also how these cells respond to stresses that result from starvation.